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Reversal of Vitamin K Antagonist (VKA) effect in patients with severe bleeding: a French multicenter observational study (Optiplex) assessing the use of Prothrombin Complex Concentrate (PCC) in current clinical practice
Desmettre, Thibaut
Dehours, Emilie
Samama, Charles-Marc
Jhundoo, Suchin
Pujeau, Frédéric
Guillaudin, Christian
Hecquart, Claudine
Clerson, Pierre
Crave, Jean Charles
Jaussaud, Roland
Critical Care
Prothrombin Complex Concentrate (PCC) is a key treatment in the management of bleeding related to Vitamin K antagonists (VKA). This study aimed to evaluate prospectively PCC use in patients with VKA-related bleeding in view of the French guidelines published in 2008.
All consecutive patients with VKA-related bleeding treated with a 4-factor PCC (Octaplex®) were selected in 33 French hospitals. Collected data included demographics, site and severity of bleeding, modalities of PCC administration, International Normalized Ratio (INR) values before and after PCC administration, outcomes and survival rate 15 days after infusion.
Of 825 patients who received PCC between August 2008 and December 2010, 646 had severe bleeding. The main haemorrhage sites were intracranial (43.7%) and abdominal (24.3%). Mean INR before PCC was 4.4 ± 1.9; INR was unavailable in 12.5% of patients. The proportions of patients who received a PCC dose according to guidelines were 15.8% in patients with initial INR 2-2.5, 41.5% in patients with INR 2.5-3, 40.8% in patients with INR 3-3.5, 26.9% in patients with INR > 3.5, and 63.5% of patients with unknown INR. Vitamin K was administered in 84.7% of patients. The infused dose of PCC did not vary with initial INR; the mean dose was 25.3 ± 9.8 IU/Kg. Rates of controlled bleeding and target INR achievement were similar, regardless of whether or not patients were receiving PCC doses as per the guidelines. No differences in INR after PCC treatment were observed, regardless of whether or not vitamin K was administered. INR was first monitored after a mean time frame of 4.5 ± 5.6 hours post PCC. The overall survival rate at 15 days after PCC infusion was 75.4% (65.1% in patients with intracranial haemorrhage). A better prognosis was observed in patients reaching the target INR.
Severe bleeding related to VKA needs to be better managed, particularly regarding the PCC infused dose, INR monitoring and administration of vitamin K. A dose of 25 IU/kg PCC appears to be efficacious in achieving a target INR of 1.5. Further studies are required to assess whether adjusting PCC dose and/or better management of INR would improve outcomes.
Related Articles
A French multicenter randomised trial comparing two dose-regimens of prothrombin complex concentrates in urgent anticoagulation reversal
Kerebel, Delphine
Joly, Luc-Marie
Honnart, Didier
Schmidt, Jeannot
Galanaud, Damien
Negrier, Claude
Kursten, Friedrich
Coriat, Pierre
Critical Care
Prothrombin complex concentrates (PCC) are haemostatic blood preparations indicated for urgent anticoagulation reversal, though the optimal dose for effective reversal is still under debate. The latest generation of PCCs include four coagulation factors, the so-called 4-factor PCC. The aim of this study was to compare the efficacy and safety of two doses, 25 and 40 IU/kg, of 4-factor PCC in vitamin K antagonist (VKA) associated intracranial haemorrhage.
We performed a phase III, prospective, randomised, open-label study including patients with objectively diagnosed VKA-associated intracranial haemorrhage between November 2008 and April 2011 in 22 centres in France. Patients were randomised to receive 25 or 40 IU/kg of 4-factor PCC. The primary endpoint was the international normalised ratio (INR) 10 minutes after the end of 4-factor PCC infusion. Secondary endpoints were changes in coagulation factors, global clinical outcomes and incidence of adverse events (AEs).
A total of 59 patients were randomised: 29 in the 25 IU/kg and 30 in the 40 IU/kg group. Baseline demographics and clinical characteristics were comparable between the groups. The mean INR was significantly reduced to 1.2 - and ≤1.5 in all patients of both groups - 10 minutes after 4-factor PCC infusion. The INR in the 40 IU/kg group was significantly lower than in the 25 IU/kg group 10 minutes (P = 0.001), 1 hour (P = 0.001) and 3 hours (P = 0.02) after infusion. The 40 IU/kg dose was also effective in replacing coagulation factors such as PT (P = 0.038), FII (P = 0.001), FX (P <0.001), protein C (P = 0.002) and protein S (0.043), 10 minutes after infusion. However, no differences were found in haematoma volume or global clinical outcomes between the groups. Incidence of death and thrombotic events was similar between the groups.
Rapid infusion of both doses of 4-factor PCC achieved an INR of 1.5 or less in all patients with a lower INR observed in the 40 IU/kg group. No safety concerns were raised by the 40 IU/kg dose. Further trials are needed to evaluate the impact of the high dose of 4-factor PCC on functional outcomes and mortality.
Trial registration
Eudra CT number 2007-000602-73.
Related Articles
Point-of-Care International Normalized Ratio (INR) Monitoring Devices for Patients on Long-term Oral Anticoagulation Therapy
Ontario Health Technology Assessment Series
Executive Summary
Subject of the Evidence-Based Analysis
The purpose of this evidence based analysis report is to examine the safety and effectiveness of point-of-care (POC) international normalized ratio (INR) monitoring devices for patients on long-term oral anticoagulation therapy (OAT).
Clinical Need: Target Population and Condition
Long-term OAT is typically required by patients with mechanical heart valves, chronic atrial fibrillation, venous thromboembolism, myocardial infarction, stroke, and/or peripheral arterial occlusion. It is estimated that approximately 1% of the population receives anticoagulation treatment and, by applying this value to Ontario, there are an estimated 132,000 patients on OAT in the province, a figure that is expected to increase with the aging population.
Patients on OAT are regularly monitored and their medications adjusted to ensure that their INR scores remain in the therapeutic range. This can be challenging due to the narrow therapeutic window of warfarin and variation in individual responses. Optimal INR scores depend on the underlying indication for treatment and patient level characteristics, but for most patients the therapeutic range is an INR score of between 2.0 and 3.0.
The current standard of care in Ontario for patients on long-term OAT is laboratory-based INR determination with management carried out by primary care physicians or anticoagulation clinics (ACCs). Patients also regularly visit a hospital or community-based facility to provide a venous blood samples (venipuncture) that are then sent to a laboratory for INR analysis.
Experts, however, have commented that there may be under-utilization of OAT due to patient factors, physician factors, or regional practice variations and that sub-optimal patient management may also occur. There is currently no population-based Ontario data to permit the assessment of patient care, but recent systematic reviews have estimated that less that 50% of patients receive OAT on a routine basis and that patients are in the therapeutic range only 64% of the time.
Overview of POC INR Devices
POC INR devices offer an alternative to laboratory-based testing and venipuncture, enabling INR determination from a fingerstick sample of whole blood. Independent evaluations have shown POC devices to have an acceptable level of precision. They permit INR results to be determined immediately, allowing for more rapid medication adjustments.
POC devices can be used in a variety of settings including physician offices, ACCs, long-term care facilities, pharmacies, or by the patients themselves through self-testing (PST) or self-management (PSM) techniques. With PST, patients measure their INR values and then contact their physician for instructions on dose adjustment, whereas with PSM, patients adjust the medication themselves based on pre-set algorithms. These models are not suitable for all patients and require the identification and education of suitable candidates.
Potential advantages of POC devices include improved convenience to patients, better treatment compliance and satisfaction, more frequent monitoring and fewer thromboembolic and hemorrhagic complications. Potential disadvantages of the device include the tendency to underestimate high INR values and overestimate low INR values, low thromboplastin sensitivity, inability to calculate a mean normal PT, and errors in INR determination in patients with antiphospholipid antibodies with certain instruments. Although treatment satisfaction and quality of life (QoL) may improve with POC INR monitoring, some patients may experience increased anxiety or preoccupation with their disease with these strategies.
Evidence-Based Analysis Methods
Research Questions
1. Effectiveness
Does POC INR monitoring improve clinical outcomes in various settings compared to standard laboratory-based testing?
Does POC INR monitoring impact patient satisfaction, QoL, compliance, acceptability, convenience compared to standard laboratory-based INR determination?
Settings include primary care settings with use of POC INR devices by general practitioners or nurses, ACCs, pharmacies, long-term care homes, and use by the patient either for PST or PSM.
2. Cost-effectiveness
What is the cost-effectiveness of POC INR monitoring devices in various settings compared to standard laboratory-based INR determination?
Inclusion Criteria
English-language RCTs, systematic reviews, and meta-analyses
Publication dates: 1996 to November 25, 2008
Population: patients on OAT
Intervention: anticoagulation monitoring by POC INR device in any setting including anticoagulation clinic, primary care (general practitioner or nurse), pharmacy, long-term care facility, PST, PSM or any other POC INR strategy
Minimum sample size: 50 patients Minimum follow-up period: 3 months
Comparator: usual care defined as venipuncture blood draw for an INR laboratory test and management provided by an ACC or individual practitioner
Outcomes: Hemorrhagic events, thromboembolic events, all-cause mortality, anticoagulation control as assessed by proportion of time or values in the therapeutic range, patient reported outcomes including satisfaction, QoL, compliance, acceptability, convenience
Exclusion criteria
Non-RCTs, before-after studies, quasi-experimental studies, observational studies, case reports, case series, editorials, letters, non-systematic reviews, conference proceedings, abstracts, non-English articles, duplicate publications
Studies where POC INR devices were compared to laboratory testing to assess test accuracy
Studies where the POC INR results were not used to guide patient management
Method of Review
A search of electronic databases (OVID MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, The Cochrane Library, and the International Agency for Health Technology Assessment [INAHTA] database) was undertaken to identify evidence published from January 1, 1998 to November 25, 2008. Studies meeting the inclusion criteria were selected from the search results. Reference lists of selected articles were also checked for relevant studies.
Summary of Findings
Five existing reviews and 22 articles describing 17 unique RCTs met the inclusion criteria. Three RCTs examined POC INR monitoring devices with PST strategies, 11 RCTs examined PSM strategies, one RCT included both PST and PSM strategies and two RCTs examined the use of POC INR monitoring devices by health care professionals.
Anticoagulation Control
Anticoagulation control is measured by the percentage of time INR is within the therapeutic range or by the percentage of INR values in the therapeutic range. Due to the differing methodologies and reporting structures used, it was deemed inappropriate to combine the data and estimate whether the difference between groups would be significant. Instead, the results of individual studies were weighted by the number of person-years of observation and then pooled to calculate a summary measure.
Across most studies, patients in the intervention groups tended to have a higher percentage of time and values in the therapeutic target range in comparison to control patients. When the percentage of time in the therapeutic range was pooled across studies and weighted by the number of person-years of observation, the difference between the intervention and control groups was 4.2% for PSM, 7.2% for PST and 6.1% for POC use by health care practitioners. Overall, intervention patients were in the target range 69% of the time and control patients were in the therapeutic target range 64% of the time leading to an overall difference between groups of roughly 5%.
Major Complications and Deaths
There was no statistically significant difference in the number of major hemorrhagic events between patients managed with POC INR monitoring devices and patients managed with standard laboratory testing (OR =0.74; 95% CI: 0.52- 1.04). This difference was non-significant for all POC strategies (PSM, PST, health care practitioner).
Patients managed with POC INR monitoring devices had significantly fewer thromboembolic events than usual care patients (OR =0.52; 95% CI: 0.37 - 0.74). When divided by POC strategy, PSM resulted in significantly fewer thromboembolic events than usual care (OR =0.46.; 95% CI: 0.29 - 0.72). The observed difference in thromboembolic events for PSM remained significant when the analysis was limited to major thromboembolic events (OR =0.40; 95% CI: 0.17 - 0.93), but was non-significant when the analysis was limited to minor thromboembolic events (OR =0.73; 95% CI: 0.08 - 7.01). PST and GP/Nurse strategies did not result in significant differences in thromboembolic events, however there were only a limited number of studies examining these interventions.
No statistically significant difference was observed in the number of deaths between POC intervention and usual care control groups (OR =0.67; 95% CI: 0.41 - 1.10). This difference was non-significant for all POC strategies. Only one study reported on survival with 10-year survival rate of 76.1% in the usual care control group compared to 84.5% in the PSM group (P=0.05).
Summary Results of Meta-Analyses of Major Complications and Deaths in POC INR Monitoring Studies
Patient Satisfaction and Quality of Life
Quality of life measures were reported in eight studies comparing POC INR monitoring to standard laboratory testing using a variety of measurement tools. It was thus not possible to calculate a quantitative summary measure. The majority of studies reported favourable impacts of POC INR monitoring on QoL and found better treatment satisfaction with POC monitoring. Results from a pre-analysis patient and caregiver focus group conducted in Ontario also indicated improved patient QoL with POC monitoring.
Quality of the Evidence
Studies varied with regard to patient eligibility, baseline patient characteristics, follow-up duration, and withdrawal rates. Differential drop-out rates were observed such that the POC intervention groups tended to have a larger number of patients who withdrew. There was a lack of consistency in the definitions and reporting for OAT control and definitions of adverse events. In most studies, the intervention group received more education on the use of warfarin and performed more frequent INR testing, which may have overestimated the effect of the POC intervention. Patient selection and eligibility criteria were not always fully described and it is likely that the majority of the PST/PSM trials included a highly motivated patient population. Lastly, a large number of trials were also sponsored by industry.
Despite the observed heterogeneity among studies, there was a general consensus in findings that POC INR monitoring devices have beneficial impacts on the risk of thromboembolic events, anticoagulation control and patient satisfaction and QoL (ES Table 2).
GRADE Quality of the Evidence on POC INR Monitoring Studies
CI refers to confidence interval; Interv, intervention; OR, odds ratio; RCT, randomized controlled trial.
Economic Analysis
Using a 5-year Markov model, the health and economic outcomes associated with four different anticoagulation management approaches were evaluated:
Standard care: consisting of a laboratory test with a venipuncture blood draw for an INR;
Healthcare staff testing: consisting of a test with a POC INR device in a medical clinic comprised of healthcare staff such as pharmacists, nurses, and physicians following protocol to manage OAT;
PST: patient self-testing using a POC INR device and phoning in results to an ACC or family physician; and
PSM: patient self-managing using a POC INR device and self-adjustment of OAT according to a standardized protocol. Patients may also phone in to a medical office for guidance.
The primary analytic perspective was that of the MOHLTC. Only direct medical costs were considered and the time horizon of the model was five years - the serviceable life of a POC device.
From the results of the economic analysis, it was found that POC strategies are cost-effective compared to traditional INR laboratory testing. In particular, the healthcare staff testing strategy can derive potential cost savings from the use of one device for multiple patients. The PSM strategy, however, seems to be the most cost-effective method i.e. patients are more inclined to adjust their INRs more readily (as opposed to allowing INRs to fall out of range).
Considerations for Ontario Health System
Although the use of POC devices continues to diffuse throughout Ontario, not all OAT patients are suitable or have the ability to practice PST/PSM. The use of POC is currently concentrated at the institutional setting, including hospitals, ACCs, long-term care facilities, physician offices and pharmacies, and is much less commonly used at the patient level. It is, however, estimated that 24% of OAT patients (representing approximately 32,000 patients in Ontario), would be suitable candidates for PST/PSM strategies and willing to use a POC device.
There are several barriers to the use and implementation of POC INR monitoring devices, including factors such as lack of physician familiarity with the devices, resistance to changing established laboratory-based methods, lack of an approach for identifying suitable patients and inadequate resources for effective patient education and training. Issues of cost and insufficient reimbursement strategies may also hinder implementation and effective quality assurance programs would need to be developed to ensure that INR measurements are accurate and precise.
For a select group of patients who are highly motivated and trained, PSM resulted in significantly fewer thromboembolic events compared to conventional laboratory-based INR testing. No significant differences were observed for major hemorrhages or all-cause mortality. PST and GP/Nurse use of POC strategies are just as effective as conventional laboratory-based INR testing for thromboembolic events, major hemorrhages, and all-cause mortality. POC strategies may also result in better OAT control as measured by the proportion of time INR is in the therapeutic range and there appears to be beneficial impacts on patient satisfaction and QoL. The use of POC devices should factor in patient suitability, patient education and training, health system constraints, and affordability.
anticoagulants, International Normalized Ratio, point-of-care, self-monitoring, warfarin.
Related Articles
Bench-to-bedside review: Optimising emergency reversal of vitamin K antagonists in severe haemorrhage – from theory to practice
Vigué, Bernard
Critical Care
Critical care physicians are increasingly facing patients receiving oral anticoagulation for either cessation of major haemorrhage or to reverse the effects of vitamin K antagonists ahead of emergency surgery. Rapid reversal of anticoagulation is particularly essential in cases of life-threatening bleeding. In these situations, guidelines recommend the concomitant administration of prothrombin complex concentrates (PCCs) and oral or intravenous vitamin K for the fastest normalisation of the international normalised ratio (INR). Despite their universal recommendation, PCCs remain underused by many physicians who prefer to opt for fresh frozen plasma despite its limitations in anticoagulant reversal, including time to reverse INR and high risk of transfusion-related acute lung injury. In contrast, the lower volume required to normalise INR with PCCs and the room temperature storage facilitate faster preparation and administration time, thus increasing the speed at which haemorrhages can be treated. PCCs therefore allow faster, more reliable and complete reversal of vitamin K anticoagulation, especially when administered immediately following confirmation of haemorrhage. In the emergency setting, probabilistic dosing may be considered.
Related Articles
Activated Prothrombin Complex Concentrates for the Reversal of Anticoagulant-Associated Coagulopathy
Awad, Nadia I.
Cocchio, Craig
Pharmacy and Therapeutics
Managing hemorrhaging after the use of warfarin and other anticoagulants is challenging. Although an FDA-approved product, FEIBA, has been used as an off-label anticoagulant-reversal agent, the potential risks of thrombosis associated with activated prothrombin complex concentrates must be carefully weighed.
Prothrombin complex concentrate (PCC) products are emerging as alternative strategies for reversing anticoagulant pharmacotherapy. Factor eight inhibitor bypassing activity (FEIBA, or anti-inhibitor coagulant complex) is an activated PCC (aPCC). Although FEIBA is approved by the FDA to control spontaneous bleeding episodes and to prevent bleeding with surgical interventions in hemophilia A and hemophilia B patients with inhibitors to factor VIII, recent data have suggested that the product may be used off-label as an anticoagulant-reversal agent. To evaluate the safety and efficacy of aPCC products in reversing anticoagulant pharmacotherapy, we searched online databases for English-language publications that discussed this topic.
Data Sources: The EMBASE, MEDLINE, and International Pharmaceutical Abstracts databases were used. We evaluated all articles published in the English language identified from the data sources. We included studies conducted in human subjects and in in vitro and in vivo models in our review.
Current published evidence suggests that the use of an aPCC, compared with fresh-frozen plasma, is associated with a significantly faster correction of supratherapeutic International Normalized Ratios (INRs) secondary to warfarin therapy. Conflicting evidence exists regarding the ability of aPCCs to reverse the prolonged bleeding times caused by the anticoagulant agents dabigatran etexilate (Pradaxa), rivaroxaban (Xarelto), apixaban (Eliquis), and fondaparinux (Arixtra).
The theoretical risks of thrombosis associated with PCC products must be carefully considered before they are administered to patients who require coagulation therapy. The use of aPCCs to reverse the anticoagulant effects of warfarin, dabigatran, or rivaroxaban should be limited because of the lack of efficacy and safety data in humans. Moreover, the safety of aPCCs in off-label indications has not been adequately assessed.
FEIBA; activated PCC; hemorrhage; reversal; anticoagulation
Related Articles
Prothrombin complex concentrate (Beriplex P/N) in severe bleeding: experience in a large tertiary hospital
Bruce, David
Nokes, Tim JC
Critical Care
Major blood loss can often be life-threatening and is most commonly encountered in the settings of surgery and trauma. Patients receiving anticoagulant therapy are also at increased risk of bleeding. We investigated the use of a prothrombin complex concentrate (PCC; Beriplex P/N, CSL Behring, Marburg, Germany) to treat severe bleeding in a variety of settings: cardiac surgery, warfarin therapy and other surgery.
Thirty consecutive patients who had received PCC were identified from blood transfusion records. For cardiac surgery and warfarin reversal, PCC was administered in accordance with hospital protocols. PCC was administered to cardiac and other surgical patients responding poorly to recognized blood products, whereas it was administered first-line to patients with life-threatening bleeds and requiring warfarin reversal, in accordance with British Committee for Standards in Haematology guidelines. We conducted a retrospective analysis of patient records in order to ascertain PCC dose, use of other blood products and response to PCC (clotting screen results before and after PCC administration, haemostasis achievement, and survival).
Six patients (20%) were excluded because of inadequate documentation (n = 5) or acquired haemophilia (n = 1). Therefore, 24 patients were included in the analysis: coronary artery bypass graft (n = 5), mitral/aortic valve replacement (n = 2), other surgery (n = 9) and warfarin reversal (n = 8). Most patients (83.3%) received no more than 1500 IU of Beriplex P/N 500. Considerable reduction in administration of other blood products was seen during the 24 hours after PCC administration. Partial or complete haemostasis was achieved in 14 out of 18 cases (77.8%). In total, 12 out of 24 patients (50%) died during the study; two-thirds of the deaths were considered unrelated to bleeding. No thrombotic complications or adverse drug reactions were observed.
This study emphasizes the value of PCC in reversing the effects of oral anticoagulant therapy in bleeding patients. It also demonstrates the potential value of PCC in controlling bleeding in patients undergoing cardiac and other surgical procedures. The use of PCC in bleeding patients without hereditary or anticoagulation-related coagulopathy is novel, and further investigation is warranted. In the future, it may be possible to use PCC as a substitute for fresh frozen plasma in this setting; adequate documentation is crucial for all blood products.
Related Articles
Real world usage of PCC to "rapidly" correct warfarin induced coagulopathy
Toth, Peter
van Veen, Joost Jair
Robinson, Kate
Maclean, Rhona Murray
Hampton, Kingsley Kevin
Laidlaw, Stuart
Makris, Michael
Blood Transfusion
Life threatening bleeding and emergency procedures in patients on vitamin K antagonists are indications for urgent reversal with prothrombin complex concentrate and vitamin K. Rapid reversal in these situations is emphasized in the literature and guidelines, but only very limited information is available on its real life use, especially on the timing of treatment in relation to presentation.
Materials and methods
We retrospectively audited emergency warfarin reversal in 131 consecutive patients. We studied the indication, use of vitamin K, time between presentation and administration of vitamin K and PCC, effectiveness in INR reduction and clinical outcome.
The median PCC dose was 26.8 IU/kg. The median INR was reduced from 3.1 to 1.2. Vitamin K (5 mg) was given in 91.6% of evaluable patients. We found significant delays in administration of PCC and vitamin K. The median time between presentation and administration of vitamin K/PCC was 3.6 and 5.2 hours respectively. The times in intracranial haemorrhage were 2.7 and 3.0 hours and in emergency procedures 17.4 and 15.9 hours respectively. Mortality related to bleeding was 7.6% overall but in patients with intracranial haemorrhage 22.8%. The thrombotic rate within 7 days of reversal was 1.5%.
The local protocol for reversal with PCC and vitamin K was adhered to well but the delay in pre-procedural patients, suggests that intravenous vitamin K alone may be sufficient in many cases and PCC administration can be avoided by better planning. Intracranial haemorrhage in warfarinised patients carries a high mortality. Treatment delays should be avoided by making PCC stocks available within emergency departments, simple dosing structures independent of INR and administering PCC without waiting for INR and CT scan results in those with strong suspicion of intracranial haemorrhage and clear trauma. Future reports and studies should always include the time from presentation to PCC treatment.
prothrombin complex concentrate; vitamin K antagonist; reversal; warfarin; haemorrhage
Related Articles
Emergency reversal of anticoagulation with a three-factor prothrombin complex concentrate in patients with intracranial haemorrhage
Imberti, Davide
Barillari, Giovanni
Biasioli, Chiara
Bianchi, Marina
Contino, Laura
Duce, Rita
D'Incà, Marco
Gnani, Maria Cristina
Mari, Elisa
Ageno, Walter
Blood Transfusion
Intracranial haemorrhage is a serious and potentially fatal complication of oral anticoagulant therapy. Prothrombin complex concentrates can substantially shorten the time needed to reverse the effects of oral anticoagulants. The aim of this study was to determine the efficacy and safety of a prothrombin complex concentrate for rapid reversal of oral anticoagulant therapy in patients with intracranial haemorrhage.
Patients receiving oral anticoagulant therapy and suffering from acute intracranial haemorrhage were eligible for this prospective cohort study if their International Normalised Ratio (INR) was higher than or equal to 2.0. The prothrombin complex concentrate was infused at doses of 35–50 IU/kg, stratified according to the initial INR.
Forty-six patients (25 males; mean age: 75 years; range 38–92 years) were enrolled. The median INR at presentation was 3.5 (range, 2–9). At 30 minutes after administration of the prothrombin complex concentrate, the median INR was 1.3 (range, 0.9–3), and the INR then declined to less than or equal to 1.5 in 75% of patients. The benefit of the prothrombin complex concentrate was maintained for a long time, since the median INR remained lower than or equal to 1.5 (median, 1.16; range, 0.9–2.2) at 96% of all post-infusion time-points up to 96 hours. No thrombotic complications or significant adverse events were observed during hospitalisation; six patients (13%) died, but none of these deaths was judged to be related to administration of the prothrombin complex concentrate.
Prothrombin complex concentrates are an effective, rapid and safe treatment for the urgent reversal of oral anticoagulation in patients with intracranial haemorrhage. Broader use of prothrombin complex concentrates in this clinical setting appears to be appropriate.
intracranial haemorrhage; oral anticoagulants; prothrombin complex concentrates
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Use of Prothrombin Complex Concentrate for Vitamin K Antagonist Reversal before Surgical Treatment of Intracranial Hemorrhage
Wong, Yun
Clinical Medicine Insights. Case Reports
Oral anticoagulant therapy (OAT) is used to prevent/treat thromboembolism. Major bleeding is common in patients on OAT; eg, warfarin increases intracranial hemorrhage (ICH) risk.
A 71-year-old male on warfarin (to reduce stroke risk) presented at Accident and Emergency Minor Injuries Unit with headache after reportedly sounding 'drunk'. On triage, the patient appeared lucid and well. However, International Normalized Ratio (INR) was 4.1. Head computed tomography (CT) indicated a large right-sided subdural hematoma. Prothrombin complex concentrate (PCC; Beriplex® P/N, CSL Behring) with vitamin K normalized the INR within minutes of administration. The patient underwent neurosurgery without complications, and was discharged after 5 days, with no residual neurological symptoms.
ICH patients can present with no neurological signs. In OAT patients with headache, INR must be established; if ≥3.0, normalization of INR and head CT are essential. PCC is the best option to rapidly reverse anticoagulation and correct INR pre-surgery.
anticoagulation reversal; Beriplex® P/N; computed tomography; International Normalized Ratio; intracranial hemorrhage; prothrombin complex concentrate
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Multivariate relationships between international normalized ratio and vitamin K-dependent coagulation-derived parameters in normal healthy donors and oral anticoagulant therapy patients
Watala, Cezary
Golanski, Jacek
Kardas, Przemyslaw
Thrombosis Journal
Background and objectives
International Normalized Ratio (INR) is a world-wide routinely used factor in the monitoring of oral anticoagulation treatment (OAT). However, it was reported that other factors, e. g. factor II, may even better reflect therapeutic efficacy of OAT and, therefore, may be potentialy useful for OAT monitoring. The primary purpose of this study was to characterize the associations of INR with other vitamin K-dependent plasma proteins in a heterogenous group of individuals, including healthy donors, patients on OAT and patients not receiving OAT. The study aimed also at establishing the influence of co-morbid conditions (incl. accompanying diseases) and co-medications (incl. different intensity of OAT) on INR.
Design and Methods
Two hundred and three subjects were involved in the study. Of these, 35 were normal healthy donors (group I), 73 were patients on medication different than OAT (group II) and 95 were patients on stable oral anticoagulant (acenocoumarol) therapy lasting for at least half a year prior to the study. The values of INR and activated partial thromboplastin time (APTT) ratio, as well as activities of FII, FVII, FX, protein C, and concentration of prothrombin F1+2 fragments and fibrinogen were obtained for all subjects. In statistical evaluation, the uni- and multivariate analyses were employed and the regression equations describing the obtained associations were estimated.
Of the studied parameters, three (factors II, VII and X) appeared as very strong modulators of INR, protein C and prothrombin fragments F1+2 had moderate influence, whereas both APTT ratio and fibrinogen had no significant impact on INR variability. Due to collinearity and low tolerance of independent variables included in the multiple regression models, we routinely employed a ridge multiple regression model which compromises the minimal number of independent variables with the maximal overall determination coefficient. The best-fitted two-component model included FII and FVII activities and explained 90% of INR variability (compared to 93% in the 5-component model including all vitamin K-dependent proteins). Neither the presence of accompanying diseases nor the use of OAT nor any other medication (acetylsalicylic acid, statins, steroids, thyroxin) biased significantly these associations.
Among various vitamin K-dependent plasma proteins, the coagulation factors II, VII and X showed the most significant associations with INR. Of these variables, the two-component model, including factors II and VII, deserves special attention, as it largely explains the overall variability observed in INR estimates. The statistical power of this model is validated on virtue of the estimation that the revealed associations are rather universal and remain essentially unbiased by other compounding variables, including clinical status and medical treatment. Further, much broader population studies are needed to verify clinical usefulness of methods alternate or compounding to INR monitoring of OAT.
International Normalized Ratio (INR) of prothrombin time; clotting factors; protein C; prothrombin fragment F1+2; multivariate analysis
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Comparison of 3-Factor Prothrombin Complex Concentrate and Low-Dose Recombinant Factor VIIa for Warfarin Reversal
Chapman, Scott A
Irwin, Eric D
Abou-Karam, Nada M
Rupnow, Nichole M
Hutson, Katherine E
Vespa, Jeffrey
Roach, Robert M
World Journal of Emergency Surgery : WJES
Prothrombin complex concentrate (PCC) and recombinant Factor VIIa (rFVIIa) have been used for emergent reversal of warfarin anticoagulation. Few clinical studies have compared these agents in warfarin reversal. We compared warfarin reversal in patients who received either 3 factor PCC (PCC3) or low-dose rFVIIa (LDrFVIIa) for reversal of warfarin anticoagulation.
Data were collected from medical charts of patients who received at least one dose of PCC3 (20 units/kg) or LDrFVIIa (1000 or 1200 mcg) for emergent warfarin reversal from August 2007 to October 2011. The primary end-points were achievement of an INR 1.5 or less for efficacy and thromboembolic events for safety.
Seventy-four PCC3 and 32 LDrFVIIa patients were analyzed. Baseline demographics, reason for warfarin reversal, and initial INR were equivalent. There was no difference in the use of vitamin K or fresh frozen plasma. More LDrFVIIa patients achieved an INR of 1.5 or less (71.9% vs. 33.8%, p =0.001). The follow-up INR was lower after LDrFVIIa (1.25 vs. 1.75, p < 0.05) and the percent change in INR was larger after LDrFVIIa (54.1% vs. 38.8%, p = 0.002). There was no difference in the number of thromboembolic events (2 LDrFVIIa vs. 5 PCC3, p = 1.00), mortality, length of hospital stay, or cost.
Based on achieving a goal INR of 1.5 or less, LDrFVIIa was more likely than PCC3 to reverse warfarin anticoagulation. Thromboembolic events were equivalent in patients receiving PCC3 and LDrFVIIa.
Anticoagulation; Hemorrhage; Trauma; Prothrombin complex concentrate; Recombinant factor VIIa; Warfarin
Related Articles
Prothrombin Complex Concentrate for Rapid Reversal of Warfarin Anticoagulation to Allow Neuraxial Blockade
Skerritt, Conor
Mannion, Stephen
Case Reports in Anesthesiology
The development of Prothrombin Complex Concentrates (PCCs) has led to better outcomes in patients receiving emergency reversal of warfarin. However, most published data describes the use of PCCs in the setting of major bleeding or emergent major surgery, with little information on neuraxial blockade. We describe a case of rapid warfarin reversal using PCC and subsequent surgery under spinal anaesthesia in an 87-year-old lady, for whom general anaesthesia was deemed high risk. Her international normalised ratio (INR) on the morning of surgery was 1.8, precluding neuraxial blockade; however, it was felt that given, the need for imminent surgery, immediate reversal of the warfarin was indicated. We administered a single dose of 23 units/kg PCC and 5 mg vitamin K. Her INR 1 hour following PCC was 1.2, and spinal anesthetic was administered. The patient then underwent excision of melanoma deposits from her leg and groin dissection. There were no complications, the patient recovered satisfactorily, and there were no thrombotic or hemorrhagic events at 30 days postoperatively. This case study demonstrates a novel use of PCCs; in certain patients, PCCs may be safely used for immediate reversal of warfarin to allow for neuraxial blockade, safer anaesthesia, and better outcomes.
Related Articles
Warfarin Anticoagulation Exacerbates the Risk of Hemorrhagic Transformation after rt-PA Treatment in Experimental Stroke: Therapeutic Potential of PCC
Pfeilschifter, Waltraud
Spitzer, Daniel
Pfeilschifter, Josef
Steinmetz, Helmuth
Foerch, Christian
PLoS ONE
Oral anticoagulant therapy (OAT) with warfarin is the standard of stroke prevention in patients with atrial fibrillation. Approximately 30% of patients with cardioembolic strokes are on OAT at the time of symptom onset. We investigated whether warfarin exacerbates the risk of thrombolysis-associated hemorrhagic transformation (HT) in a mouse model of ischemic stroke.
62 C57BL/6 mice were used for this study. To achieve effective anticoagulation, warfarin was administered orally. We performed right middle cerebral artery occlusion (MCAO) for 3 h and assessed functional deficit and HT blood volume after 24 h.
In non-anticoagulated mice, treatment with rt-PA (10 mg/kg i.v.) after 3 h MCAO led to a 5-fold higher degree of HT compared to vehicle-treated controls (4.0±0.5 µl vs. 0.8±0.1, p<0.001). Mice on warfarin revealed larger amounts of HT after rt-PA treatment in comparison to non-anticoagulated mice (9.2±3.2 µl vs. 2.8±1.0, p<0.05). The rapid reversal of anticoagulation by means of prothrombin complex concentrates (PCC, 100 IU/kg) at the end of the 3 h MCAO period, but prior to rt-PA administration, neutralized the exacerbated risk of HT as compared to sham-treated controls (3.8±0.7 µl vs. 15.0±3.8, p<0.001).
In view of the vastly increased risk of HT, it seems to be justified to withhold tPA therapy in effectively anticoagulated patients with acute ischemic stroke. The rapid reversal of anticoagulation with PCC prior to tPA application reduces the risk attributed to warfarin pretreatment and may constitute an interesting therapeutic option.
Related Articles
Rapid reversal of anticoagulation reduces hemorrhage volume in a mouse model of Warfarin-associated intracerebral hemorrhage
Foerch, Christian
Arai, Ken
Van Cott, Elizabeth Merrill
van Leyen, Klaus
Lo, Eng H
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism
Warfarin-associated intracerebral hemorrhage (W-ICH) is a severe type of stroke. There is no consensus on the optimal treatment for W-ICH. Using a mouse model, we tested whether the rapid reversal of anticoagulation using human prothrombin complex concentrate (PCC) can reduce hemorrhagic blood volume. Male CD-1 mice were treated with warfarin (2 mg/kg over 24 h), resulting in a mean (±s.d.) International Normalized Ratio of 3.5±0.9. First, we showed that an intravenous administration of human PCC rapidly reversed anticoagulation in mice. Second, a stereotactic injection of collagenase was administered to induce hemorrhage in the right striatum. Forty-five minutes later, the animals were randomly treated with PCC (100 U/kg) or saline IV (n = 12 per group). Twenty-four hours after hemorrhage induction, hemorrhagic blood volume was quantified using a photometric hemoglobin assay. The mean hemorrhagic blood volume was reduced in PCC-treated animals (6.5±3.1 μL) compared with saline controls (15.3±11.2 μL, P = 0.015). In the saline group, 45% of the mice developed large hematomas (i.e., > 15 μL). In contrast, such extensive lesions were never found in the PCC group. We provide experimental data suggesting PCC to be an effective acute treatment for W-ICH in terms of reducing hemorrhagic blood volume. Future studies are needed to assess the therapeutic potential emerging from our finding for human W-ICH.
anticoagulation; intracerebral hemorrhage; mouse model; warfarin
Related Articles
Recombinant Activated Coagulation Factor VII and Prothrombin Complex Concentrates Are Equally Effective in Reducing Hematoma Volume in Experimental Warfarin-Associated Intracerebral Hemorrhage
Schlunk, Frieder
Van Cott, Elizabeth M.
Hayakawa, Kazuhide
Pfeilschifter, Waltraud
Lo, Eng H.
Foerch, Christian
Stroke; a journal of cerebral circulation
Background and Purpose
Based on an experimental model of warfarin-associated intracerebral hemorrhage, we investigated whether the rapid reversal of anticoagulation using prothrombin complex concentrates (PCC) or recombinant activated coagulation factor VII (rFVIIa) reduces hematoma volume.
Mice were orally pretreated with warfarin (2 mg/kg). Intracerebral hemorrhage was induced by collagenase injection into the right striatum. Forty-five minutes later, PCC (100 IE/kg), rFVIIa (1 mg/kg), or an equal volume of saline was administered intravenously. Hematoma volume after 24 hours was quantified using a photometric hemoglobin assay.
International normalized ratio was 4.3 ± 0.4 in saline-treated mice, 0.9 ± 0.1 in rFVIIa mice, and 1.4 ± 0.2 in PCC mice. Intracerebral hemorrhage volume was 29.0 ± 19.7 µL in the saline group (n = 7), 8.6 ± 4.3 µL in the rFVIIa group (n = 6), and 6.1 ± 1.8 µL in the PCC group (n = 7; analysis of variance between-group differences P = 0.004; post hoc rFVIIa versus saline P = 0.021; PCC versus saline P = 0.007). No significant difference was found between PCC- and rFVIIa-treated animals.
Our results suggest that PCC and rFVIIa are equally effective in restoring coagulation and preventing excessive hematoma growth in acute warfarin-associated intracerebral hemorrhage.
animal models; anticoagulation; ICH; intracerebral hemorrhage; warfarin
Related Articles
Prothrombin complex concentrate in surgical patients: retrospective evaluation of vitamin K antagonist reversal and treatment of severe bleeding
Schick, Kerstin S
Fertmann, Jan M
Jauch, Karl-Walter
Hoffmann, Johannes N
Critical Care
Prothrombin complex concentrates are recommended for rapid reversal of vitamin K anticoagulants. As they normalize levels of vitamin K dependent clotting factors and re-establish hemostasis, they may also be used as adjunctive therapy in patients with major bleeding. The aim of this study was to retrospectively evaluate the efficacy of prothrombin complex concentrates in the surgical setting.
The case notes of 50 patients requiring urgent oral anticoagulation reversal (n = 12) or with severe perioperative coagulopathic bleeding (n = 38) who received an infusion of prothrombin complex concentrate (Beriplex P/N(R) 500) at the surgical department of the University of Munich Hospital, Germany were retrospectively reviewed. Efficacy of prothrombin complex concentrate application was evaluated using the Quick test, reported as an international normalized ratio, hemodynamic measurements and requirement for blood products. Safety assessments included whole blood hemoglobin levels and specific parameters of organ dysfunction.
Baseline characteristics were comparable, except that mean baseline international normalized ratio and hemoglobin levels were significantly higher (P < 0.01) in anticoagulation reversal than in bleeding patients. In anticoagulation reversal, the international normalized ratio was significantly reduced (from 2.8 +/- 0.2 at baseline to 1.5 +/- 0.1, P < 0.001) after one prothrombin complex concentrate infusion (median dose 1500 IU; lower quartile 1,000, upper quartile 2,000). No major bleeding was observed during surgery after prothrombin complex concentrate administration. Only one patient received platelets and red blood cell transfusion after prothrombin complex concentrate administration. In bleeding patients, infusion of prothrombin complex concentrate (median dose 2,000 IU; lower quartile 2,000, upper quartile 3,000) significantly reduced the INR from 1.7 +/- 0.1 at baseline to 1.4 +/- 0.1 (P < 0.001). This decrease was unrelated to fresh frozen plasma or vitamin K administration. Bleeding stopped after prothrombin complex concentrate administration in 4/11 (36%) patients with surgical bleeding and 26/27 (96%) patients with diffuse bleeding. Hemoglobin levels increased significantly from baseline in bleeding patients (P < 0.05) and mean arterial pressure stabilized (P < 0.05). No thrombotic events or changes in organ function were reported in any patient.
Prothrombin complex concentrate application effectively reduced international normalized ratios in anticoagulation reversal, allowing surgical procedures and interventions without major bleeding. In bleeding patients, the improvement in coagulation after prothrombin complex concentrate administration was judged to be clinically significant.
Related Articles
Prothrombin complex concentrates and a specific antidote to dabigatran are effective ex-vivo in reversing the effects of dabigatran in an anticoagulation/liver trauma experimental model
Grottke, Oliver
van Ryn, Joanne
Spronk, Henri MH
Rossaint, Rolf
Critical Care
New oral anticoagulants are effective alternatives to warfarin. However, no specific reversal agents are available for life-threatening bleeding or emergency surgery. Using a porcine model of trauma, this study assessed the ability of prothrombin complex concentrate (PCC), activated PCC (aPCC), recombinant FVIIa (rFVIIa) and a specific antidote to dabigatran (aDabi-Fab) to reverse the anticoagulant effects of dabigatran.
Dabigatran etexilate (DE) was given orally for 3 days (30 mg/kg bid) and intravenously on day 4 to achieve consistent, supratherapeutic concentrations of dabigatran. Blood samples were collected at baseline, after oral DE, after intravenous dabigatran, and 60 minutes post-injury. PCC (30 and 60 U/kg), aPCC (30 and 60 U/kg), rFVIIa (90 and 180 μg/kg) and antidote (60 and 120 mg/kg) were added to blood samples ex-vivo. Coagulation was assessed by thromboelastometry, global coagulation assays and diluted thrombin time.
Plasma concentrations of dabigatran were 380 ± 106 ng/ml and 1423 ± 432 ng/ml after oral and intravenous administration, respectively, and all coagulation parameters were affected by dabigatran. Both PCCs and aDabi-Fab, but not rFVIIa, reversed the effects of dabigatran on thromboelastometry parameters and prothrombin time. In contrast, aPTT was only normalised by aDabi-Fab. Plasma concentration (activity) of dabigatran remained elevated after PCC and rFVIIa therapy, but was not measureable after aDabi-Fab.
In conclusion, PCC and aPCC were effective in reducing the anticoagulant effects of dabigatran under different conditions, while aDabi-Fab fully corrected all coagulation measures and decreased the plasma concentration of dabigatran below the limit of detection. No significant effects were observed with rFVIIa.
Related Articles
INR reduction after prothrombin complex concentrate (Co-fact©) administration: comparison of INR outcomes in different patient categories at the emergency department
Roodheuvel, Floris
Ligtenberg, Jack JM
ter Maaten, Jan C
International Journal of Emergency Medicine
Co-fact©, prothrombin complex concentrate, is used for restoring the international normalized ratio (INR) in patients on vitamin K antagonists (VKA) presenting with acute bleeding. In this prospective cohort study, we evaluated whether adequate INR values were reached in ED patients using the Sanquin (Federation of Dutch Thrombosis Services) treatment protocol.
We evaluated this protocol for two target INR groups: group 1, target INR ≤ 1.5 (for life-threatening bleeding/immediate intervention); group 2, target INR 1.6-2.1 (in cases of a minor urgent surgery or serious overdosing of anticoagulant). We specifically wanted to identify both under- and over-treated patients. Reversing VKA anticoagulation therapy to unnecessarily low INR values may involve thrombotic risks. Apart from this risk, the patient is also administered an excess amount of the drug. This means unnecessary costs and may present problems with restoring an anticoagulated state at a later time.
In our cohort, the Sanquin dosing protocol was followed for 45/60 patients. It appeared that out of the 41 patients in group 1 (target INR ≤ 1.5), 35 (85%) achieved the goal INR. This occurred more often than for the 19 patients in group 2 (target INR 1.6–2.1), where only 6 (32%) achieved the goal INR. Using the protocol resulted in a positive trend toward better INR reversal in group 1.
In group 2, no relation between using the protocol and achieving the desired INR value was detected. Physicians ignoring the proposed dose of Co-fact© prescribed significantly less Co-fact© (even when correcting for patient weight). It appeared that patients in group 1 had a significantly lower baseline INR than patients in group 2. Group 2 patients, on the other hand, had a baseline INR > 7.5 in 53% of the cases.
In our cohort, for most patients in INR group 2 treated with Co-fact©, the achieved INR value was outside the desired range of 1.6-2.1. The supra-therapeutic range of baseline INR in group 2 may have contributed to the different kind of bleeding witnessed in this patient group.
Our results support the idea that treatment of patients on vitamin K antagonists with Co-fact© could benefit from a slightly different approach, taking into account the INR value to which the patient needs to be reversed.
Related Articles
A review of the clinical utility of INR to monitor and guide administration of prothrombin complex concentrate to orally anticoagulated patients
Sølbeck, Sacha
Ostrowski, Sisse R
Johansson, Pär I
Thrombosis Journal
Background and objectives
The number of patients treated with oral anticoagulation (OAC) is increasing and these patients are monitored by International Normalized Ratio (INR). Bleeding complications are common and we speculate if this is related to the limitation of INR only reflecting the initiation steps of the haemostatic process. The objective of the present review was to reassess the evidence for using INR as a tool to guide administration of prothrombin complex concentrates (PCC) to OAC patients. A Medline and Cochrane database search was conducted using the following keywords: prothrombin complex concentrate, reversal of oral anticoagulation and international normalized ratio (INR). Thirty-three articles were contracted and a total of ten studies were eligible after applying inclusion and exclusion criteria encompassing only 339 patients. No consensus regarding optimal target INR value to aim for when reversing OAC was found. In three of the studies it was reported that patients reaching their target INR continued to bleed, whereas three studies reviewed reported good haemostatic response also in patients that did not reach their target INR. The present review found limited evidence for the usefulness of INR as a tool to monitor and guide reversal of OAC induced coagulopathy in patients with PCC, which is expected given that it is a plasma-based assay only reflecting a limited part of the haemostatic process.
INR; PCC; OAC; Anticoagulation reversal; Haemostatic efficacy
Related Articles
Correlation between International Normalized Ratio values and sufficiency of two different local hemostatic measures in anticoagulated patients
Amer, Mohamed Zaghlool
Mourad, Samah I.
Salem, Ahmed S.
Abdelfadil, Ehab
European Journal of Dentistry
The management of patients receiving oral anticoagulant therapy (OAT) undergoing minor oral surgeries is controversial. This study was designed to evaluate the correlation between International Normalized Ratio (INR) values and the sufficiency of two different local hemostatic measures in controlling postextraction bleeding in anticoagulated patients.
Materials and Methods:
One hundred and sixty patients receiving Warfarin OAT were included in this study. Patients were selected so that 80 patients have INR values of ≤2, whereas the remaining patients have the INR values ranging from 2 to 3. Forty patients were then randomly selected from each category to form two equal groups. Forty-five patients who had never been on OAT were selected as a negative control group (group 1). Failure to achieve hemostasis using a pressure pack was managed using either tranexamic acid (group 2) or Ankaferd Blood Stopper (ABS) (group 3).
The INR values of patients included in group 2 and 3 ranged from 1.5 to 3, with a mean of 2.2. No significant difference was recorded between the use of either tranexamic acid or ABS in achieving hemostasis in anticoagulated patients with INR values ranging between 2 and 3 (P = 0.93).
Based on our findings, ABS is a hemostatic agent of good efficacy. The effect of ABS in controlling post-extraction bleeding in anticoagulated patients with INR values ≤3 is comparable to tranexamic acid with no evidence to support the superiority of tranexamic acid over ABS.
Gel foam; postextraction bleeding; tranexamic acid; warfarin; ankaferd
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Patients' perspectives on self-testing of oral anticoagulation therapy: Content analysis of patients' internet blogs
Shah, Syed Ghulam Sarwar
Robinson, Ian
BMC Health Services Research
Patients on oral anticoagulant therapy (OAT) require regular testing of the prothrombin time (PT) and the international normalised ratio (INR) to monitor their blood coagulation level to avoid complications of either over or under coagulation. PT/INR can be tested by a healthcare professional or by the patient. The latter mode of the testing is known as patient self-testing or home testing. The objective of this study was to elicit patients' perspectives and experiences regarding PT/INR self-testing using portable coagulometer devices.
Internet blog text mining was used to collect 246 blog postings by 108 patients, mainly from the USA and the UK. The content of these qualitative data were analysed using XSight and NVivo software packages.
The key themes in relation to self-testing of OAT identified were as follows: Patient benefits reported were time saved, personal control, choice, travel reduction, cheaper testing, and peace of mind. Equipment issues included high costs, reliability, quality, and learning how to use the device. PT/INR issues focused on the frequency of testing, INR fluctuations and individual target (therapeutic) INR level. Other themes noted were INR testing at laboratories, the interactions with healthcare professionals in managing and testing OAT and insurance companies' involvement in acquiring the self-testing equipment. Social issues included the pain and stress of taking and testing for OAT.
Patients' blogs on PT/INR testing provide insightful information that can help in understanding the nature of the experiences and perspectives of patients on self-testing of OAT. The themes identified in this paper highlight the substantial complexities involved in self-testing programmes in the healthcare system. Thus, the issues elicited in this study are very valuable for all stakeholders involved in developing effective self-testing strategies in healthcare that are gaining considerable current momentum particularly for patients with chronic illness.
Related Articles
A non-experimental study of oral anticoagulation therapy initiation before and after national patient safety goals
Beadles, Christopher A
Hassmiller Lich, Kristen
Viera, Anthony J
Greene, Sandra B
Brookhart, M Alan
Weinberger, Morris
BMJ Open
The Joint Commission revised its National Patient Safety Goals (NPSGs) to include oral anticoagulation therapy (OAT) in 2008. We sought to examine the effect of including OAT in The Joint Commission's NPSGs on historically low rates of OAT initiation for individuals with incident atrial fibrillation (AF).
Southeastern state in the USA.
North Carolina State Health Plan claims data from 944 500 individuals enrolled between 1 January 2006 and 31 December 2010, supplemented with data from the Area Resource File and Online Survey, Certification and Reporting data network. We evaluated OAT initiation before and after the 2008 NPSGs revisions in a retrospective cohort new user design with an AF intervention group and two control groups: a positive control—patients estimated to be at very high risk of thromboembolism (mechanical heart valve and pulmonary embolism); and a negative control—patients with very low perceived risk of thromboembolism (paroxysmal AF). We developed multivariable models using a difference-in-difference parameterisation. Effects were estimated with generalised estimating equations.
Primary outcome measure
OAT initiation, a binary outcome defined as having a prescription drug claim for warfarin within 30 days of the index claim.
OAT initiation was low (26.8%) for eligible individuals with incident AF in 2006–2008 but increased after NPSGs implementation (31.7%, p=0.022). OAT initiation was high but decreased in the positive control group (67.5% vs 62.0%, p=0.003). Multivariate analysis resulted in a relative 11% (95% CI (4% to 18%), p<0.01) increase in OAT initiation for incident AF patients.
We document a substantial increase in guideline concordant OAT initiation in incident AF after the establishment of NPSGs, suggesting that regulatory healthcare agency initiatives can influence clinical practice.
Related Articles
A sensitivity comparison of the Quick and Owren prothrombin time methods in oral anticoagulant therapy
Horsti, Juha
Hematology Reviews
Prothrombin time (PT) is the leading test for monitoring oral anticoagulation therapy (OAT). According to the World Health Organization recommendation, International Normalized Ratio (INR) results obtained from the same patient samples with the major PT methods (Quick and Owren) should be the same when the therapeutic range is the same. In our study blood samples were obtained from 207 OAT patients. We analyzed the samples using two Quick and two Owren PT (combined thromboplastin) reagents for INR and assessed the sensitivity and true coagulation activity using a new-generation PT method. The INR values with the Quick PT and Owren PT methods were very similar around the normal range, while unacceptable differences were seen within the therapeutic range and at higher INR values. The Quick PT results as INR are clearly lower than those given by Owren PT and the difference increases toward higher INR. The new PT method functions well with both Owren PT reagents, and we can calculate the true active INR. The Quick PT methods show no sensitivity to coagulation inhibition measurement. The harmonization of the INR is an important goal for the safety of OAT patients. More accurate INR results reduce morbidity and mortality, and the therapeutic ranges should be similar worldwide. In this study we found unacceptable differences in INR results produced by the two PT methods. The new method showed a lack of sensitivity to Quick PT. For the global harmonization of OAT therapy and for INR accuracy only the more sensitive Owren PT method should be used.
International Normalized Ratio; oral anticoagulant therapy; prothrombin time; warfarin.
Related Articles
Oral anticoagulation in elderly patients as secondary prevention of cardioembolic strokes
Benavente, Lorena
Calleja, Sergio
de la Vega, Vanessa
García, Jorge
Lahoz, Carlos H
International Archives of Medicine
Stroke incidence increases with age. Atrial fibrillation (AF) is an important risk factor for ischemic stroke and its incidence also increases with age. However oral anticoagulant therapy (OAT) tends to be underused in the elderly population.
Elderly patients (> = 80 years) with an ischemic stroke admitted in our department between 1/7/2003 and 31/6/2005 were prospectively evaluated. Baseline characteristics, risk factors, treatment and etiology according to TOAST criteria were recorded. Patients treated with OAT were followed up in order to assess any side effect and stroke recurrence. Mean follow-up was of 19.5 months (7-45) from discharge.
Sixty four out of a hundred and fifty nine elderly patients (40.25%) were classified as cardioembolic; mean age was 84.5 years (80-97) and 64.6% were women. AF had been previously identified in 60% of them (16.9% were on OAT and 40.6% on antiplatelet therapy). At discharge, 32 patients (49.2%) were on OAT. In the follow-up 4 patients (12.5%) suffered systemic haemorrhages (3 urinary, 1 gastrointestinal bleeding), with no change in their functional status. Mean INR in this group was 5.9 [3-11] and, in 3 of them, OAT was cancelled. No brain haemorrhages were recorded. Ischemic stroke recurred in 4 patients (INR < 1.8 in 3 of them; the other, INR 2.35). Three patients had died at the end of the follow-up, one of them as a consequence of ischemic stroke recurrence.
Twenty eight point eight of stroke patients admitted in the period of study were >80 years. The high proportion of cardioembolic strokes in this age segment contrasts with the general underuse of OAT as antithrombotic prophylaxis. Our study suggests that OAT is a safe strategy when carefully prescribed, even for elderly patients.
Related Articles
Warfarin for non-rheumatic atrial fibrillation: five year experience in a district general hospital
Yousef, Z R
Tandy, S C
Tudor, V
Jishi, F
Trent, R J
Watson, D K
Cowell, R P W
Objectives: To assess the long term efficacy of and risks associated with computer aided oral anticoagulation for non-rheumatic atrial fibrillation (NRAF) in a district hospital setting.
Design: Retrospective, age stratified, event driven clinical database analysis.
Setting: District general hospital.
Participants: 739 patients receiving warfarin for NRAF between 1996 and 2001. Patients were selected from an anticoagulation database through appropriate filter settings.
Main outcome measures: Anticoagulation control (international normalised ratio (INR)) and hospitalisations for bleeding complications, thromboembolic events, and stroke.
Results: Over 1484 patient-years, computer assisted anticoagulation was uncontrolled in 38.3% of patients (INR < 2.0 or > 3.0). No significant differences in INR control were observed with respect to patient age (< 65, 65–75, and > 75 years), although to achieve adequate control of anticoagulation, the frequency of testing increased significantly with age. Annual risks of bleeding complications, thromboembolism, and stroke were 0.76%, 0.35%, and 0.84%, respectively. No significant differences in these events were observed between the three age groups studied. Patients who had thromboembolic events and haemorrhagic complications were significantly more likely to have been under-anticoagulated (INR < 2.0) and over-anticoagulated (INR > 3.0), respectively, at the time of their clinical event.
Conclusions: Computerised long term oral anticoagulation for NRAF in a community setting of elderly and diverse patients is safe and effective. Anticoagulation control, bleeding events, thromboembolic episodes, and stroke rates are directly comparable with those reported in major clinical trials. The authors therefore support the strategy of rate control with long term oral anticoagulation for NRAF in general clinical practice.
atrial fibrillation; warfarin; long term oral anticoagulation
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The District is responsible for the quality of water flowing through the canals and swales of San Carlos Estates. The purpose of the District is to work with our neighbors and engineer to maintain our NPDES (National Pollutant Discharge Elimination System) permit.
"Notice is hereby given that a position is open for election to the Board of Supervisors for the San Carlos Estates Water Control District. If you wish to obtain more information about the position that is open for election, you may contact the District office at 239-495-4699. The deadline to notify the District of your intent to quality is July 15, 2016, at 5:00 p.m."
Monthly Meeting date changed to July 26, 2016, 6:00 pm Trianon Bonita Bay.

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If you are considering transferring to Sacred Heart University, we've compiled all of the information you'll need to answer frequently asked questions about our campus. Once you have had the opportunity to learn more about the University, please schedule a visit to campus. You will never know if we are the right fit for you until you meet us in person.
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We look forward to working with you and encourage you to reach out by phone or email with any questions:
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Forensic Engineering & Building Science Services
For over 35 years, clients have trusted Crane Engineering to provide expert, multi-disciplined forensic engineering and consulting services for industrial applications, insurance claims, subrogation and product liability litigation.
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|David Sean Taylor <da...@bluesunrise.com>
|Re: Jetspeed Cache Question
|Tue, 06 Nov 2007 06:03:11 GMT
On Nov 5, 2007, at 1:30 PM, Sie, Yang wrote: > I had my page loaded with data, my portlet sizes and my other personal > data are correctly displayed, they were all from preferences. So I > thought my preferences would be loaded by then. I just now went to > edit > to change some preference, and then run that section of code again, it > again returned me all zeros. by default Spring doesn't share its CacheManager (you can set the "share" property to true on the cacheManager bean in the Spring config (cache.xml) Or, using the Spring container's cache manager will give you accurate numbers : <%@page import="org.apache.jetspeed.Jetspeed"%> <%@page import="org.apache.jetspeed.components.ComponentManager"%> <% // CacheManager ehCacheManager=CacheManager.getInstance(); CacheManager ehCacheManager=(CacheManager) Jetspeed.getComponentManager().getComponent("cacheManager"); --------------------------------------------------------------------- To unsubscribe, e-mail: email@example.com For additional commands, e-mail: email@example.com
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I entered my room to discover my five-year-old grandson looking up at a large crucifix on the wall above my bed. He turned and asked if that really happened. "Yes it did," I replied.
Read the rest of entry »
The moral life of a Christian is beautiful because it is inspired by communion with the aspirations of humanity to goodness and happiness, said the primate of the Church in Canada.
EDMONTON - Controversy over the Canadian Catholic Organization for Development and Peace has created "an awful lot of hysteria" on both sides of the issue, says Archbishop Richard Smith.
The foundational beauty of moral theology is that it stands on the belief that every person is made in God's image, a leading Catholic ethicist told the annual convention of the Edmonton Diocesan Council of the Catholic Women's League.
VATICAN CITY – Citing "serious doctrinal problems which affect many in consecrated life," the Vatican announced a major reform of an association of women's religious congregations in the U.S.
VATICAN CITY – The reform of the Leadership Conference of Women Religious will offer the sisters and their bishops an opportunity to work together more closely, said the archbishop who will oversee the reform.
RED DEER – A year into her two-year term as president of the Edmonton Diocesan Council of the Catholic Women's League, Gladys Brown seems remarkably relaxed, although she admits to been busier than expected.
Growing up in Vietnam, Father Huy Nguyen, was one of 13 children, 10 of whom were girls. He always looked forward to Mass because he could socialize afterwards with other boys. He felt so good being at church that he was in no hurry to return home.
When Montreal Archbishop Christian Lépine is installed April 27 in Canada's second largest diocese, the event inaugurates a new era for the Quebec episcopacy.
Let me begin by saying how proud and happy I am to be standing before you today to speak about the beauty of the moral life. Not only does the subject appeal to me for its importance in our lives but also for the timing of this presentation.


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The Kate Upton GQ Magazine GIF Collection
I did my best to extract every possible gif from Kate Upton's GQ magazine extravaganza for you filthy animals.
Check out more articles on BuzzFeed.com!
More News About Kate Upton
Preview Your Response
In The News Today
- Hillary Clinton's campaign was reportedly hacked as part of what appears to be a broad cyber attack on Democrats.
- Two brothers suspected of planning terror attacks have been arrested in Belgium, prosecutors say.
- Four people in Florida are likely the first to contract the Zika virus from mosquitos in the US, the state's governor says.


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Here is our suggested route for a train journey between West Acton and East Acton station:
Journey: West Acton → North Acton → East Acton
Estimated time: 10 mins
Fare zones: 2, 3 (what is the train fare?)
Return journey: East Acton to West Acton station
Remember to check if your journey will be affected by train strikes or engineering works
Note: Closures, cancellations or delays might affect your journey and you should allow for extra time on top
London: A Visitor's Guide
Have you seen our eBook? It has a beginner's guide to using London's buses, boats, taxis and trains, including all the fares
1,000+ pages filled with money-
saving tips, maps and reviews
For the fare between West Acton station and East Acton, see zones 2 and 3 fares
Buy an Underground ticket Buy an Oyster Card (more info)
Buy a Visitor Oyster Card (info)
Buy a Travelcard (more info)
Buy a Travelcard + London Pass
Contactless payment cards
Alternative train stations nearby:
North Ealing to East Acton, Park Royal to East Acton or Ealing Common to East Acton
Alternative train stations nearby:
West Acton to North Acton, West Acton to White City or West Acton to Wood Lane


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5J Cinco Jotas: paleta ibérica de bellota
Cinco Jotas (5J) is the unquestioned standard-bearer of Spanish gastronomy. Known unabashedly as "the finest ham in the world", these limited-production hams are so sought after that distributors must reserve and pay for them 2-3 years in... read more
La Gleva Sausages Sampler Pack
This is a great way to try out the best of La Gleva's sausages hand-made from their organically-raised, free-range pigs. They are hands-down the best cured pork sausages we've tasted. As they are all-natural (no synthetic or cellulose casings... read more
Beher Gold Label: Jamón ibérico de bellota
Diet of acorns and other wild plants, free-range in the Dehesa
Weight: 7,5 - 8,0 kg
Gold Medal winner for 3 consecutive IFFA events... read more
Seafood Tapas Party Pack
Turn your dining room into a tapas bar in Galicia. Just add cold Spanish beer, toothpicks, and friends.
The Seafood Tapas Party Pack consists of:
2 x Noly Mejillones en Escabeche (mussels in sweet and sour sauce), 111g net... read more
C&G 100g: Hand sliced Jamón ibérico de bellota
Every one of the acorn-fed iberian hams produced by the respected house of Castro y González is a work of craftsmanship and tradition. This particular ham, from the prestigious region... read more
Our ham
Spanish ham, or jamón, is one of the world's gastronomic treasures. Hamlovers sells the best ham from all of Spain's ham-producing regions.


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3 mm 10k White Gold Men's Wedding Band
If you are looking for a wedding band for a man that "doesn't like wearing jewelry" than this is it. Simple, comfortable, looks good on the hand.
- How did the image on site compare with the actual product? actual
- How accurate was the sizing? due to it's slim 3 mm construction it fits 1/2 size larger
- Please tell us about the quality of the product. good quality
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Size too small
The ring fits small. In addition It seems more like 2 mm.
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Welcome to the Laurel football team wall. The most current information will appear at the top of the wall dating back to prior seasons.
Utilize the left navigation tools to find past seasons, game schedules, rosters and more. Best of luck this fall! Visit Laurel's Team Preview
Looking for 2015 info?
Plenty of top-rated talent and elite defensive backs help make up the nation's team of the best medium-school players. Read Article Get Notified
Plenty of blue-chip talent on Top 25 teams helps make up the nation's All-American defensive and all-purpose team. Read Article Get Notified
The Laurel football team preview, complete with returning player information and program history is available. Visit Laurel's Team Preview
Led by two of the nation's top 60 recruits and a strong 2019 class, the Stags appear ready for another national title run. Read Article Get Notified
The Stags look to stand out in the tough Washington Catholic Athletic Conference. Read Article Get Notified
Though California has been biggest producer of Washington's draft picks, Texas players have made biggest impact. Read Article Get Notified
Kyle Snyder defeats former Olympic champion Jake Varner to punch ticket to Rio Olympic Games. Read Article Get Notified
Get Notified
MaxPreps' football rankings have been updated.
Laurel's national rank has moved -9. View Rankings Get Notified


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|Comic Viewers
|Webcomic Aggregators
|Make Your Own
ACMEreader 0.09
This comic viewer / comic reader lets you read your daily comics with ease.
- ACMEreader stores comic strips in an archive.
- ACMEreader keeps track of new and read comic strips.
New strips are shown in a different color.
- Small fonts can be read more easily with the zoom tool.
- Navigation can be done smoothly with mouse and keyboard.
Comic Life 1.4.1
Comic Life gives you a super-quick and easy way to create astounding comics, beautiful picture albums and enticing instruction booklets to name a few of the many possibilities.
Included are professional and fun templates, ready to drag and drop onto your page for instant attractive photo layouts. Or if you like to be in control, position your photos and panels how you like and save them for later use.
Comics 2.0.2
Comics is a Mac Os X Application that helps you to organize your personal comics collection: Title, Series, Pages, Authors etc... A simple system of image catching can help you to include the cover image of the comic with a Drag & Drop and the List Viewer let's you see all the comics in archive.
Comictastic 2.3.2
Comictastic automatically grabs your favorite comics from the web, giving you unprecedented comic reading efficiency. Save yourself hours of mucking through the vasty deadwood of unfunny guff and syndicated slag; invigorate your life with fresh humor-infused morsels assembled in one easy-to-use application.
Support for 10 breathtakingly humorous comics built right in.
Your favorite comic isn't supported? No problem! Just type in the URL and relax. No awkward plug-ins or HTML knowledge necessary.
RSS and Atom support for comics that provide feeds (you can also use this feature to read news feeds, in a gimpy sort of way).
Download comic archives to easily catch up on missed days.
Save comics on your disk for later browsing using the handy built-in calendar.
FFView 0.9.9
FFView is a fast OpenGL-powered picture viewer a la ACDsee (2.x). It is aimed at letting you read manga or other comics onscreen (windowed & fullscreen mode). Features include fast prefetching, smooth panning, voice commands, 2-page mode, a magnifying lens, the ability to browse pictures inside archives (.rar/.cbr, .zip/.cbz) and sticky per-picture options. It reads EXIF tags and is scriptable.
French Kiss 18.104.22.168
For viewing KISS files (anime). French Kiss is graphics software that lets you work with graphics in a whole new way. Instead of viewing a static picture, you can decide what you like and create your own drag-and-drop, roll-your-own graphics! In a nutshell, you can dress up cute anime girls in a variety of scenes, which can even include sound and animation, and pick and choose what you enjoy. Pretty much like computerized paper dolls.
iComic 3.0.3
Easy to use interface, works like Apple's Safari browser.
Subscribe to your favorite web comics, then collect the latest strips from them.
Easy to use tabs to flip between the comic you subscribe to.
Open architecture, supports plugins written in the Perl language.
A plugin may return a single image or a whole set (such as from an archive page)
Windows sizes to fit the comic you're viewing.
Add comments to a strip, then find a strip based on your comments.
Add strips you like to a list of Favorites
iStrip 1.5.11
An application to view and archive comic strips available online
- Download comic strip images and cache them for offline viewing
- Support for over 500 strips built in
- Keyboard navigation provides quick access to strips and dates
- Save bookmarks for your favourite strips
- Strip images can be saved or dragged to disc, or to other applications
- Automatically pre-fetch all available images for a strip
Jomic 0.9.30
Jomic is a viewer for comic book archives. It can handle both CBZ and CBR archives and has a two page mode. Supported image formats are PNG, JFIF/JPEG, TIFF, and GIF. It is Open Source software distributed under the GNU General Public License.
Manga Studio 3.0
Manga Studio, the world's leading manga and comic art software, gives you the power and flexibility to easily create professional-quality comics, manga and illustrations. Manga Studio 3.0 is your all-in-one solution for professional, ready-to-publish manga and comics from start to finish, all with easy-to-use tools, filters and special effects.
Please note that files saved from the Manga Studio trial version will not be accessible in the full version.
Sequential 2.1.2
Sequential is a fullscreen image viewer for Mac OS X. It was specifically designed for opening a folder of images and displaying them in order. It works well for viewing comics and manga on the computer.
Sequential can display folders and archives (ZIP, RAR, CBZ and CBR) of images (including JPG, PNG, and GIF) in addition to PDF files. Starting with version 1.3, Sequential is able to open images on the internet from a page or image URL.
Simple Comic 1.7
Page Layout - Pages laid out as they would be in print
Page Ordering - Left to right or right to left
Page Scaling - Original size, window fit, horizontal fit and defined height
Fullscreen - Maximize viewing area
Archive Handling - Seamlessly deals with .cbr, .cbz, .zip, .rar, tar, 7z, lha and others
PDF Handling - Opens PDF based comics
Multiple Sessions - View multiple comics at one time
Auto-save - Comics are automatically bookmarked and reopened at launch
Page Rotation - Rotate the pages to maximize display area
Wednesday's List 1.5.5
In short, Wednesday's List is a powerful application designed to help comic book collectors view, manage, print, and save custom new and upcoming comic book release pull lists.
To be more specific, Wednesday's List downloads the current week's shipping list (as well as those expected to ship the following week) from RAILhead Design's server, and once downloaded, it allows you to browse through all the available titles. You simply select the titles you're interested in and use Wednesday's List to print out your selections, save them as a text file, export them to iCal, sync them to your handheld, or email them to anyone you want. Basically, it's a comic book pull list creator and manager on steroids.
Denotes Mac OS X Intel Native
Denotes Mac OS X Intel & PPC Native
Denotes Mac OS X PPC Native
Denotes Mac OS 8/9 PPC Native
Denotes Mac OS 680x0 Native
Denotes Non-OS Specific Code


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Google Voice is a Voice over IP (VoIP) service that allows users to send and receive calls to and from computers and cell phones, as well as other mobile devices. Google Voice also provides 'visual voice mail' by transcribing voice messages to text for easy management. Google Voice provides ...
641 views
What are the internal workings of Google Voice?
I am new to Google Voice and am interested in how it works internally so I have few doubts about it. Is the Google Voice number itself a SIP number? How does Google Voice receive calls from any PSTN ...


text: SPRING STREET LLC v. APOSTOL, ARNOLD & LUCAS, N. JOHN January 4, 2013 share share on linkedin Facebook share on twitter share on google+ Share With Email Send Thank you for sharing! Your article was successfully shared with the contacts you provided. print reprints Appellate Term, First Judicial Department 170 Dec 19 2012 (Date Decided) By: Lowe, III, P.J., Schoenfeld, Shulman, J.J. 170 SPRING STREET LLC v. APOSTOL, ARNOLD & LUCAS, N. JOHN — It is Ordered that landlordrespondent's motion to dismiss the appeal is granted, unless appellants perfect their appeal by no later than the April 2013 term-the filing deadline is February 5, 2013. In the event of appellants' failure to comply with the foregoing condition, landlordrespondent may move on five days' notice for an order dismissing the appeal. More from the ALM Network Previous Next Kim Kardashian vs. Taylor Swift: The Legal Implications of the Snapchat Recording Williams & Connolly Argues to Block Clinton from Questioning The National Law Journal Georgia's Same-Sex Adoption Is Valid in Alabama, US Supreme Court Says Daily Report The Quotable Thomas Perez: Secretary of Labor and Possible VP Pick Corporate Counsel How Women Can Be Assertive (and Lovable) Why We Kicked Dentons Off the NLJ 500 and Am Law 200 Lists The National Law Journal Brexit Fallout Begins for the Legal Industry Texas and Volkswagen Shake Hands on $50M Partial Settlement Texas Lawyer Updated: Supreme Court Strikes Down Abortion Restrictions in Texas In-House Lawyers Slam Order Requiring Yelp to Take Down Reviews Corporate Counsel Ali's Lawyers, Counsel to The Champ, Recall Representing The Greatest The Am Law Daily Headed Back to Class, Ken Starr Faces Trust Issues, Experts Say The National Law Journal Verrilli, Who Defended Obama Policies in Landmark Cases, is Leaving Justice Department Yelp Review of Pet-sitting Company Protected by Free-Speech, Defendants Argue Texas Lawyer When It Comes to Workplace Bullying, Jurisdiction Matters Corporate Counsel Law Firms Look for Lessons—and Clients—in Panama Papers Leak The Am Law Daily George Mason Law Faculty Declares Support for School's 'Scalia' Name Change The National Law Journal A Call for Legal Ops to Ditch the Silos and Share Corporate Counsel Judge Grewal to Leave Bench for Facebook The Recorder Supreme Court Decision Returns Beloved Dog to Owner Texas Lawyer More From New York Law Journal Countdown to New York's First Uniform Bar Exam Jackson Lewis Lands 39-Member Wilson Elser Lobbying Group Lawyers Again Seek to Snare Firms and Trump With Claims Queens Prosecutors See Tactics Scrutinized by Second Department


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It's been a long time since I've touched my 1up page. Here's the update:
I'm working in the industry now. I do Customer Experience, Support, Social Media and dabble in Marketing at GarageGames for InstantAction.com.
It's pretty much the best things ever.
I gave up on trying to use this site's system to upload my collection. Instead, you can find it here:


text: Stephen Colbert Catches Up on Romney's Etch A Sketch ProblemMatt Toder3/27/12 12:05amFiled to: Colbert ReportStephen ColbertMitt Romneyetch a sketchTelevisionTweetgTweetdFb4EditInvite manuallyPromoteDismissUndismissHideShare to KinjaToggle Conversation toolsGo to permalink While he was on vacation last week, Mitt Romney's communication director said his candidate's views were written on an Etch a Sketch and his opponents jumped on the claim, using it as evidence that Romney will say anything to win the nomination. But Stephen sees things a little differently: to him, it means that Romney has all the courage in the world and that comparing Romney to old toys will save the economy on account of Etch a Sketch's sales recently going through the roof. [Colbert Nation]Reply4 repliesLeave a reply


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"We forget ourselves and our destinies in health, and the chief use of temporary sickness is to remind us of these concerns."
Related quotes
"I am reminded of a colleague who reiterated "all my homosexual patients are quite sick" - to which I finally replied "so are all my heterosexual patients";"
"Then turn your back upon them for you are not to blame; / And continue to remind, for surely the reminder profits the believers."
"Two nights ago, my son's Iphone was stolen. He kept saying "its ok, my possessions don't define me" and I said to him, you keep saying that as though you have to convince yourself, we laughed it off. But truthfully, we have to keep reminding ourselves of the things that are important in life or we could very easily take it for granted. Do you need a reminder today?"
"The numbers and figures can be disputed, but the essential purpose is not only to remind our future generation not to commit all that happened here, again in East Timor, but also to remind the international community to try to do everything so that it doesn't happen again elsewhere."
"People ask me who he reminds me of. The way he's playing, I'd say he doesn't remind me of anybody. I've never seen anybody -- running back, quarterback, wide receiver -- make the plays that Vince Young made today."


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Welcome to Merivale Medical Practice. Merivale Medical Practice is a friendly general practice dedicated to providing high quality care to you and your family. We offer a comprehensive service focusing on a team approach to maintaining the wellness of our patients and managing illnesses and injuries. New patients welcome.
2016 Seasonal Influenza Vacines are available now for $35 each
They are FREE to people with certain medical conditions, people over 65 and pregnant women.
You will need to remain at the practice to watch for allergic reactions for 20 minutes after your immunisation.


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Here it comes; the Chicago Blackhawks' inevitable surge on home ice. Facing elimination from the Stanley Cup playoffs, this force of nature only gets stronger.
Wednesday's Game 6 begins about 8 p.m. ET at United Center, where the Blackhawks expect their fans to be loud and supportive. TV: NBCSN, CBC, TVA Sports.
MORE: Rangers force Game 7 vs. Lightning | Game 6 preview, odds
The Anaheim Ducks know its coming. They know the Blackhawks will attack from the puck drop. They also know they must continue to answer Chicago's physical challenge.
Winning won't be easy for either team. While the Ducks continue to pound the Blackhawks, especially their defensemen, they must watch goalie Frederik Andersen, who was exposed in Game 5.
Tuesday's game, Blackhawks winger Brandon Saad said, "was obviously tough to lose like we did. We did a good job of coming back. We know we got to have a better start and finish strong. We have to take care of our home game here and go back on the road and steal one on the road."
There are lessons for the Ducks in that victory. Here's a key: Coach Bruce Boudreau said his players must "stay in the moment. You got to stay focused at what's at hand. If you start thinking ahead, usually bad things happen."
MORE: Playoff action images | Video highlights | Game 5: Ducks blow lead, win in OT
"We know what it takes," Ducks winger Corey Perry told The Orange County Register. "We know how hard it is to get that fourth win. Chicago's not going to be any different. They're going to throw their best at us. We've got to be prepared."
Blackhawks coach Joel Quenneville: "We've been in some tough spots before and put ourselves back. In this series we've been behind for the third time. Putting ourselves in the spot of trying to have to win one game. That's our mindset.
"We know that they got a pretty good hockey team there, but we have to play our best game. We can talk about different things going into games, you can visit history, you can look at past games, big games, big moments. There's a lot of history here that we've collected over seven years. A lot of positive things."
Chicago is 6-1 at home during the playoffs, outscoring opponents 25-17. Its loss: Game 3 against the Ducks.
Anaheim is 4-2 on the road, outscoring opponents 23-18.
How big is the first goal? The team that scored first has each game in this series. The Ducks are 7-0 when scoring first; and Blackhawks are 7-1.


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"This edition incorporates changes consistent with our digital age, while maintaining the excellent content that has been the hallmark of this book through the years. The digital age has made information much more immediate, much easier to access and much more flexible in how it is presented... Through the decades, this book has remained and will remain one of the gold standard books in plastic surgery. Plastic Surgoens at all stages in their careerscan benefit from this book."
Journal of Plastic, Reconstructive & Aesthestic Surgery (JPRAS), January 2014
"This is the latest edition of the multivolume plastic surgery textbook first edited by John M. Converse in 1964. Through the decades, this has remained the gold standard in plastic surgery textbooks. I have always had the most recent edition close to my desk and have used it as an initial reference when I have needed to review a topic. I will continue to use this edition in the same manner.
Plastic surgeons at all stages in their careers can benefit from this book. The coverage of plastic surgery topics remains encyclopedic, and all of the authors are recognized experts in their subject areas. This edition demonstrates a number of differences from prior editions. The books themselves are slightly larger, and the majority of the artwork is in color, with a uniform style and is of high quality. This edition incorporates changes consistent with our digital age, while maintaining the excellent content that has been the hallmark of this book throughout the years." - Walter Lawrence, MPH, MD (University of Iowa Hospitals and Clinics) Doody 5 stars!


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Luna Jade > Beauty Suspended > Painted Skies > Glowing Peaceful > Glowing Peaceful Posters
A peaceful sunset on the beach in Naples, Florida.
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